JPS631314B2 - - Google Patents
Info
- Publication number
- JPS631314B2 JPS631314B2 JP52158647A JP15864777A JPS631314B2 JP S631314 B2 JPS631314 B2 JP S631314B2 JP 52158647 A JP52158647 A JP 52158647A JP 15864777 A JP15864777 A JP 15864777A JP S631314 B2 JPS631314 B2 JP S631314B2
- Authority
- JP
- Japan
- Prior art keywords
- triamino
- pteridine
- general formula
- compounds
- triamterene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims description 40
- -1 pteridine compound Chemical class 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 229960001288 triamterene Drugs 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 230000001882 diuretic effect Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 9
- 235000012239 silicon dioxide Nutrition 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- QNJVMSASTUDLGC-UHFFFAOYSA-N 4-(2,4,7-triaminopteridin-6-yl)phenol Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=C(O)C=C1 QNJVMSASTUDLGC-UHFFFAOYSA-N 0.000 description 7
- 239000002934 diuretic Substances 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 208000004880 Polyuria Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000029142 excretion Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- LNMQRZRWVQDPIB-UHFFFAOYSA-N [4-(2,4,7-triaminopteridin-6-yl)phenyl] acetate Chemical compound C1=CC(OC(=O)C)=CC=C1C1=NC2=C(N)N=C(N)N=C2N=C1N LNMQRZRWVQDPIB-UHFFFAOYSA-N 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- VMBRYBBPGMAXEJ-UHFFFAOYSA-N 2-[4-(2-hydroxyethoxy)phenyl]acetonitrile Chemical compound OCCOC1=CC=C(CC#N)C=C1 VMBRYBBPGMAXEJ-UHFFFAOYSA-N 0.000 description 4
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 4
- 229940093475 2-ethoxyethanol Drugs 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- RFBACHVOZKQPJR-UHFFFAOYSA-N 2-[4-(2,4,7-triaminopteridin-6-yl)phenoxy]ethanol Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=C(OCCO)C=C1 RFBACHVOZKQPJR-UHFFFAOYSA-N 0.000 description 3
- XLQQJSWJHHKLOK-UHFFFAOYSA-N 5-nitrosopyrimidine-2,4,6-triamine Chemical compound NC1=NC(N)=C(N=O)C(N)=N1 XLQQJSWJHHKLOK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000003293 cardioprotective effect Effects 0.000 description 3
- 229940030606 diuretics Drugs 0.000 description 3
- 210000004051 gastric juice Anatomy 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000004922 lacquer Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000009103 reabsorption Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 210000005239 tubule Anatomy 0.000 description 3
- AYKYOOPFBCOXSL-UHFFFAOYSA-N (4-hydroxyphenyl)acetonitrile Chemical compound OC1=CC=C(CC#N)C=C1 AYKYOOPFBCOXSL-UHFFFAOYSA-N 0.000 description 2
- 239000004925 Acrylic resin Substances 0.000 description 2
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 2
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229960002478 aldosterone Drugs 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 150000007658 benzothiadiazines Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 210000003079 salivary gland Anatomy 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- SVICYSRQUWDSTO-UHFFFAOYSA-N 2-nitrosopyrimidine-4,5,6-triamine Chemical compound NC1=NC(N=O)=NC(N)=C1N SVICYSRQUWDSTO-UHFFFAOYSA-N 0.000 description 1
- IUHCATHBKLBCRH-UHFFFAOYSA-N 3-[4-(2,4,7-triaminopteridin-6-yl)phenoxy]propane-1,2-diol Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=C(OCC(O)CO)C=C1 IUHCATHBKLBCRH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 208000005223 Alkalosis Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000013038 Hypocalcemia Diseases 0.000 description 1
- 206010020955 Hypochloraemia Diseases 0.000 description 1
- 208000019025 Hypokalemia Diseases 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 244000062793 Sorghum vulgare Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- ZVEKWQJEZUFXHU-UHFFFAOYSA-N [4-(cyanomethyl)phenyl] acetate Chemical compound CC(=O)OC1=CC=C(CC#N)C=C1 ZVEKWQJEZUFXHU-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 230000002340 alkalosis Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002576 amiloride Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
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- 239000003246 corticosteroid Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 230000000705 hypocalcaemia Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- YLGXILFCIXHCMC-JHGZEJCSSA-N methyl cellulose Chemical compound COC1C(OC)C(OC)C(COC)O[C@H]1O[C@H]1C(OC)C(OC)C(OC)OC1COC YLGXILFCIXHCMC-JHGZEJCSSA-N 0.000 description 1
- 235000019713 millet Nutrition 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000011294 monotherapeutic Methods 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- SUSQOBVLVYHIEX-UHFFFAOYSA-N o-phenylene-diaceto-nitrile Natural products N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 210000003540 papillary muscle Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 208000024896 potassium deficiency disease Diseases 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003195 pteridines Chemical class 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Springs (AREA)
Description
本発明は、新規プテリジン化合物に関する。
利尿作用物質の古典的な適応分野は、浮腫治療
である。良好な治療効果は、例えば塩分***剤
（狭義には：塩分***作用を直接に腎臓細管中へ
のナトリウム再吸収の阻止によつて発揮し、アニ
オン、主として塩素イオンとして***する物質）
を用いて得られた。
塩分***剤の血圧低下作用の発見で、適応分野
は著しく拡大された。殊に因果関係のある治療が
なくかつ全ての高血圧症の約80％に達する特発性
血圧亢進症の治療の場合、塩分***剤は確固たる
地位を有する。このグループの重要な代表例は、
クロロチアジド及びヒドロクロロチアジドのよう
なベンゾチアジアジン誘導体である。患者の電解
質代謝に影響があるために、ベンゾチアジアジン
誘導体の使用は不利な制約を受ける。当面の肝臓
ないしは腎臓疾患の場合、このグループの作用物
質による治療は、実際重大な危険を意味する。更
に、継続使用の際には危険な電解質−及び液体代
謝障害（低塩素血症、低カルシウム血症、低カリ
ウム血症及びアルカロージス）が発生しうる。特
に望ましくないのは、塩分***剤の単独治療的使
用の場合におけるカリウムイオンの損失である。
従つて、“カリウム節約性”利尿剤を開発する
ことが試みられた。目的方向は、（正常の物質代
謝において生理的に有意義に）腎臓細管中のナト
リウム再吸収及びカリウム分泌を促進する副腎皮
質ホルモン アルドステロンの競合的阻止にあ
る。この目的は、ステロイド誘導体スピロノラク
トンで若干達成されたが、治療には大きい用量が
要求される（１日あたり0.2〜１ｇ）。競合的アル
ドステロン阻止に関する作用のない他の“カリウ
ム節約性”利尿剤として、アミロリド（Ｎ−アミ
ジノ−３・５−ジアミノ−６−クロル−ピラジン
−カロキサミド）及びトリアムテレン（２・４・
７−トリアミノ−６−フエニルプテリジン）が見
い出された。
トリアムテレンは、浮腫及び高血圧治療におい
て単独治療ならびに例えば塩分***剤と組合せて
極めて重要な作用物質であることが証明された。
引続き、トリアムテレンの作用機構及び物質代謝
に関する実験が行なわれた。ネズミの唾液腺の主
***管（その上皮は機能上末梢腎臓細管に類似す
る）のモデル実験で、トリアムテレンがナトリウ
ムイオン再吸収を完全に遮断し、カリウムイオン
分泌が半分に減少することが判明した。唾液腺排
泄管のモデル実験は、腎臓における所見と完全に
一致して進行し、トリアムテレン作用型の“カリ
ウム節約性”利尿作用の確実な指標と見なすこと
ができる〔H.Knauf他、“Europ.J.Clin.Invest.”
第６巻、第43頁、1976年参照〕。さらに、トリア
ムテレンは心臓保護効果を有する。トリアムテレ
ンの不整脈防止効果は、モルモツトの摘出された
乳頭筋の心筋単繊維につき電気生理学的測定によ
つて証明することができる。〔B.Ju¨deritz他、
“Verh.Dtsch.Ges.Kreislaufforschung”、第41巻、
第305頁、1975年〕。
トリアムテレンは副作用の点でも利尿剤の治療
上の要件を良好に満足するが、なお良好な作用物
質を求めて実験はさらに進んだ。トリアムテレン
の看過できない欠点は、例えばその水溶性が僅か
で、有効な、腸管外適用が不可能であるというこ
とである。それで、プテリジン構造から出発し
て、置換基を系統的に変えて、構造と（利尿）作
用との間の関係を求める実験が実施された〔J.
Weinstock他、J.Med.Chem.第11巻、第573頁〜
第579頁、1968年〕。
これらの実験には、トリアムテレンの公知の代
謝基質の１つである２・４・７−トリアミノ−６
−（ｐ−ヒドロキシフエニル）−プテリジンも使用
された。この場合所見では、利尿作用が認められ
なかつた（Weinstock他、上記文献、第578頁以
降）。
検査したトリアムテレン誘導体が顕著な利尿作
用を示した限りでは、例えばトリアムテレンのｐ
−トルイル同族体のような非極性置換基を有する
ような化合物であつた。これに反して、極性基、
例えばアミノ基又はニトロ基を有する誘導体は、
ワインシユトツク（Weinstock）の所見によれば
（上記文献第表）利尿作用を有しない。
意外なことに、一般式：
〔式中Ｒは水素又は薬学的に無害な塩を表わす〕
で示される２・４・７−トリアミノ−６−（ｐ−
ヒドロキシフエニル）−プテリジン（Ａ）はす
でに僅かな濃度で顕著な利尿及びカリウム保留効
果が有していることが見出された。この場合、カ
リウム節約作用は定量試験でトリアムテレンの作
用よりも顕著である。また、化合物２・４・７−
トリアミノ−６−（ｐ−ヒドロキシフエニル）−プ
テリジンは、ヒドロキシル化されていない物質
（トリアムテレン）と比較して、殊に生理的に認
容性塩の形で改良された水溶性を示す。
更に、一般式中Ｒが主として、SO3H−基及
びそれから誘導された塩を除く親水性基を表わす
化合物、即ち一般式Ｂ：
で示される化合物は、化合物Ａの一般的作用方
向にある薬学的に使用しうる特性を有する。但
し、R′は基低級アルカノイルオキシ基、（モノ−
もしくはポリ−）ヒドロキシアルキルオキシ基を
表わすか又はカルボキシ基によつて置換されたア
ルカノイル基を表わす。一般式Ｂの化合物が特
にすぐれており、該化合物は化合物トリアムテレ
ンならびに一般式Ａの化合物に比して改良され
た水溶性を有する。
一般式Ａの化合物の製造は公知であるかもし
くは公知方法によつて行なうことができる。一般
式Ｂの化合物の製造は、自体公知方法で、例え
ば
(a) 化合物２・４・６−トリアミノ−５−ニトロ
ソ−ピリミジン（式の化合物）と一般式：
〔式中、Ｒは水素又は薬学的に無害な塩あるい
は低級アルカノイル基、（モノ−もしくはポリ
−）ヒドロキシアルキル基又はカルボキシルに
よつて置換されたアルキル基を表わす〕で示さ
れる置換フエニルアセトニトリル化合物との反
応によるか、又は一般にあまり使用されない方
法として
(b) 一般式：
XR
〔式中、Ｒは上記のものを表わし、Ｘはアシル
化／アルキル化の際に離脱基として作用するも
の、特に塩素、臭素もしくはＲが
The present invention relates to novel pteridine compounds. A classic field of indication for diuretics is the treatment of edema. A good therapeutic effect is achieved by, for example, salt excretion agents (in a narrow sense: substances that exert their salt excretion action by directly inhibiting sodium reabsorption into renal tubules and are excreted as anions, primarily chloride ions).
Obtained using With the discovery of the blood pressure lowering effect of salt excretion agents, the field of application has been significantly expanded. Particularly in the treatment of idiopathic hypertension, which has no causal treatment and accounts for approximately 80% of all hypertension cases, salt excretion agents have a strong position. Important representatives of this group are:
benzothiadiazine derivatives such as chlorothiazide and hydrochlorothiazide. The use of benzothiadiazine derivatives is disadvantageously limited due to their effect on electrolyte metabolism in patients. In the case of current liver or kidney diseases, treatment with active substances of this group actually represents a significant risk. Furthermore, with continued use, dangerous electrolyte and fluid metabolic disorders (hypochloremia, hypocalcemia, hypokalemia and alkalosis) can occur. Particularly undesirable is the loss of potassium ions in the case of monotherapeutic use of salt excretion agents. Attempts have therefore been made to develop "potassium sparing" diuretics. The goal is to competitively inhibit the corticosteroid aldosterone, which promotes sodium reabsorption and potassium secretion in the renal tubules (with physiological significance in normal metabolism). This objective has been somewhat achieved with the steroid derivative spironolactone, but treatment requires large doses (0.2-1 g per day). Other "potassium-sparing" diuretics without effects on competitive aldosterone blockade include amiloride (N-amidino-3,5-diamino-6-chloro-pyrazine-caroxamide) and triamterene (2,4-diamino-6-chloro-pyrazine-caroxamide).
7-triamino-6-phenylpteridine) was discovered. Triamterene has proven to be a very important agent in the treatment of edema and hypertension, both as a monotherapy and in combination with e.g. salt excretion agents.
Subsequently, experiments were conducted on the mechanism of action and metabolism of triamterene. Model experiments in the main excretory duct of the murine salivary gland, whose epithelium is functionally similar to peripheral renal tubules, showed that triamterene completely blocked sodium ion reabsorption and reduced potassium ion secretion by half. Model experiments in the salivary gland excretory duct proceed in complete agreement with the findings in the kidney and can be considered as a reliable indicator of the “potassium-sparing” diuresis of the triamterene-acting type [H. Knauf et al., “Europ.J. .Clin.Invest.”
See Vol. 6, p. 43, 1976]. Additionally, triamterene has cardioprotective effects. The antiarrhythmia effect of triamterene can be demonstrated by electrophysiological measurements on myocardial single fibers of isolated papillary muscles of guinea pigs. [B. Ju¨deritz et al.
“Verh.Dtsch.Ges.Kreislaufforschung”, Volume 41,
No. 305, 1975]. Although triamterene satisfies the therapeutic requirements of a diuretic well in terms of side effects, further experiments were carried out in search of a more effective substance. A considerable disadvantage of triamterene is, for example, its low water solubility, which precludes effective parenteral application. Therefore, starting from the pteridine structure, experiments were carried out by systematically varying the substituents to determine the relationship between structure and (diuretic) action [J.
Weinstock et al., J.Med.Chem. Vol. 11, pp. 573~
No. 579, 1968]. These experiments included 2,4,7-triamino-6, one of the known metabolic substrates of triamterene.
-(p-hydroxyphenyl)-pteridine was also used. In this case, no diuretic effect was observed (Weinstock et al., supra, pp. 578 et seq.). Insofar as the tested triamterene derivatives showed significant diuretic effects, for example, triamterene p
-It was a compound having a non-polar substituent such as a toluyl analogue. On the other hand, polar groups,
For example, derivatives having an amino group or a nitro group,
According to the findings of Weinstock (Table 1 of the above-mentioned literature), it has no diuretic effect. Surprisingly, the general formula: [In the formula, R represents hydrogen or a pharmaceutically harmless salt]
2,4,7-triamino-6-(p-
It has been found that hydroxyphenyl)-pteridine (A) has a pronounced diuretic and potassium-sparing effect even at low concentrations. In this case, the potassium-sparing effect is more pronounced than that of triamterene in quantitative tests. Also, compound 2, 4, 7-
Triamino-6-(p-hydroxyphenyl)-pteridine exhibits improved water solubility compared to non-hydroxylated substances (triamterene), especially in the form of physiologically acceptable salts. Furthermore, compounds in which R in the general formula mainly represents a hydrophilic group excluding the SO 3 H- group and salts derived therefrom, that is, the general formula B: The compounds shown have pharmaceutically usable properties that are in the general direction of action of Compound A. However, R' is a lower alkanoyloxy group, (mono-
Alternatively, it represents a poly-)hydroxyalkyloxy group or an alkanoyl group substituted with a carboxy group. Compounds of the general formula B are particularly preferred, which have an improved water solubility compared to the compound triamterene as well as to the compounds of the general formula A. The preparation of compounds of general formula A is known or can be carried out by known methods. The compound of general formula B can be produced by a method known per se, for example, by combining (a) compound 2,4,6-triamino-5-nitroso-pyrimidine (compound of formula) with general formula: A substituted phenylacetonitrile compound represented by the formula [wherein R represents hydrogen or a pharmaceutically harmless salt, or an alkyl group substituted with a lower alkanoyl group, a (mono- or poly-)hydroxyalkyl group, or a carboxyl group] or as a less commonly used method (b) with the general formula: Chlorine, bromine or R
【式】
（但し、R1は水素又は場合によつては炭素原
子数１〜４を有する枝分れしたアルキル基を表
わす）を表わす場合に、[Formula] (wherein R 1 represents hydrogen or optionally a branched alkyl group having 1 to 4 carbon atoms),
【式】
基（但し、R2は一般にR1基と同じ意味を有す
る）をも表わす〕で示される化合物と、Ｒがナ
トリウム又はカリウムのようなアルカリカチオ
ンを表わす（一般式A′の化合物）か、又は
Ｒが水素を表わす一般式Ａで示される化合物
とを酸受容体の存在下に反応させることによつ
て行なうことができる。
一般式Ｂの化合物の製造に使用することので
きる方法及び反応条件の選択は、特にそれぞれ式
Ａ、、及びの出発物質の相対的な入手し
易さならびに副生成物形成の確率（例えば、アミ
ノ官能基の反応による）、分離及び後処理を実施
することのできる容易さに関する考慮に依存す
る。例えば変法(a)による合成の条件下で置換基Ｒ
は十分に安定であることに注意すべきである。
方法(a)による一般式Ｂの化合物の製造は、次
のように行なうことができる：
式の化合物を反応条件下で不活性な適当な反
応媒体、例えばジメチル−ホルムアミド又はＮ・
Ｎ−ジメチル−アセトアミド中で、特にアルカリ
金属水酸化物又はアルカリ金属アミドもしくは低
級アルコールのアルカリアルコラートの存在下
に、例えば２−エトキシエタノールのようなアル
コキシアルカノールもしくはメタノール中で高め
た温度で、場合によつては懸濁液中で一般式の
化合物と反応させる。
反応時間は、例えば還流温度で作業する場合に
一般にできるだけ短くする。後処理は常法で行な
うことができる。
抽出物及び／又は最終製品の分解は、例えば可
能な反応温度の下限で作業するか、例えばカリウ
ム−第３級ブトキシドのような僅かな求核性を有
するアルカリ金属アルコラートを使用することに
よつて予防することができる。
この場合、方法(b)によつて一般式Ｂの化合物
の製造は、次のように行なうことができる：適当
な不活性溶剤、例えばアセトニトリルのようなニ
トリル、Ｎ・Ｎ−ジメチルホルムアミド、ヘキサ
メチル燐酸トリアミドのようなアミド、第３級ブ
タノールのようなアルコール、ピリジン、Ｎ・Ｎ
−ジメチルアニリンのようなアミン、場合によつ
ては溶剤の混合物ないしは懸懸液中の一般式
A′の化合物に、有利に撹拌しながら室温と120℃
ないしは溶剤の沸点との間の温度で一般式の化
合物を、場合によつては前記のような適当な溶剤
中で場合によつては酸受容剤、例えばトリエチル
アミン、Ｎ・Ｎ−ジメチルアニリン、Ｎ−メチル
モルホリンのような第３級アミンの添加下に加え
る。
該反応を完結させるためになお一定時間、例え
ば２〜24時間撹拌し、その後バツチを常法で後処
理することができる。
一般式Ａの化合物中でＲが水素を表わす場合
及び一般式の化合物XRがカルボキシル基を含
有する場合には、一般式Ｂに変換するための反
応（水脱離下）は縮合剤、特にジシクロヘキシル
カルボジイミドの使用下で行なう。反応は、アセ
トン、ピリジン等のような適当な絶対無水の不活
性溶剤中で、特に加熱しながら場合によつては例
えば14日のような長時間にわたつて実施すること
ができる。
一般式A′、、及びの出発化合物は周
知であるかないしは該化合物は公知方法によつて
又は自体公知方法と同様に製造することができ
る。
一般式の化合物は、一般に比較的高融点の結
晶性化合物である（部分的に分解）。該化合物は
例えば水溶液から、場合によつてはホルムアミ
ド、アセトニトリルを添加し、場合によつては蟻
酸、酢酸又は燐酸のような酸をも添加して再結晶
することができる。
式Ａの化合物（２・４・７−トリアミノ−６
−（ｐ−ヒドロキシ−フエニル）−プテリジン＝
“ｐ−ヒドロキシ−トリアムテレン”）及びその生
理学的に認容性の塩、殊にナトリウム塩、カリウ
ム塩、リチウム塩、ならびに生理学的に危険のな
い（薬理的作用が同じ）塩基及び禁忌作用のない
アミン及びグアニジン、例えばＮ−アルキル置換
エタノールアミン及び（塩基性）誘導体、ならび
にプロパノール−２−アミン及び（塩基性）誘導
体との塩及び一般式Ｂの化合物は、重要な医薬
である。該化合物は、カリウム保留作用と同時に
すぐれた利尿作用ならびに腎外性、殊に心臓保護
作用を有する。ｐ−ヒドロキシ−トリアムテレン
が顕著である。
該化合物は技術水準、例えばトリアムテレンよ
りもすぐれており、従つて真の技術の豊富化を表
わす。利尿作用とカリウム保留作用とを直接に比
較するためには、クナウフ（Knauf）（上記文献
中）によるネズミの顎下リンパ腺の主***管の上
皮についての研究を使用することができる。心臓
保護効果の指標として、例えばリユーデリツツ
（Lu¨deritz）（上記文献中）によるモルモツト及び
イヌの摘出された心臓組織の電気生理学的研究を
利用することができる。
更に、一般式の化合物は、良好な水溶性のた
めにトリアムテレンよりもすぐれている。著しく
改良された水溶性は、一般に強い造塩作用（強塩
基性又は酸性）を有する基を有する一般式の化
合物において考慮される。
この点で、特にフエノール化酸素に対してβ位
中にアミン残基ないしはアンモニウム基が存在す
るような、一般式Ｂの化合物を挙げることがで
きる。特に、ｑがフエノール化酸素に対しβ位中
に窒素原子が存在するように定められている一般
式Ｂの化合物が挙げられる。
従つて、適当な治療剤での本発明による一般式
の化合物は、殊に該化合物が塩の形で存在する
場合、経口投与の他に腸管外投与にも好適であ
る。
一般式の化合物は適応症の種類及び患者の個
人的必要性によつて配量することができる。
トリアムテレンに比して改良された利尿作用の
結果、実地において使用される用量は一般にトリ
アムテレンの用量よりも低い；従つて、トリアム
テレンの常用量を一般式の作用物質の用量範囲
の上限と考えることができる。
新規の化合物から医薬調剤は常法で製造するこ
とができ、該調剤は普通の担体及び助剤を含有す
ることができる。該調剤は、例えば錠剤、カプセ
ル、糖衣丸等のような経口投与に好適な固体調剤
である。経口投与には、担体材料として、例えば
マンニツト、乳糖、有機又は無機カルシウム塩等
のような薬学的に不活性の固体物質を使用するこ
とができる。結合剤としては、特にポリビニルピ
ロリドン、ゼラチン又はセルロース誘導体が好適
である。その他の添加剤としては、例えば澱粉又
はアルギン酸のような錠剤崩壊剤、例えばステア
リン酸又はその塩のような滑剤、及び例えばタル
ク又はコロイド状珪酸のような無機の流動剤、な
らびに味覚調整剤等を使用することができる。
作用物質は常法で助剤と混合し、湿潤又は乾燥
状態で顆粒にすることができる。使用した添加剤
の種類に従つて、場合によつては単なる混合によ
つて直接に錠剤にしうる粉末を得ることもでき
る。顆粒又は粉末はそのままカプセルに詰める
か、又は常法で錠剤芯にプレス成形することがで
きる。
腸管外投与の場合、治療剤を同様に常法で調製
し、投与することができる。
次の実施例は、一般式Ｂの化合物の製造を詳
説するために使用されるが、本発明は該方法に限
定されるものではない。
製造例
１ ２・４・７−トリアミノ−６−（ｐ−アセト
キシ−フエニル）−プテリジンの製造
金属ナトリウム410mgを撹拌下で２−エトキ
シ−エタノール100ml中に溶かす。これに撹拌
しながら順次に２・４・６−トリアミノニトロ
ソピリミジン1100mg及びｐ−アセトキシベンジ
ル−シアニド1140mgを加え、撹拌しながら沸騰
するまで加熱する。混合物の色は、紫色から褐
色に変わる。還流下に２時間沸騰した後、加熱
を中止し、反応混合物を冷却させる。引続き、
２−エトキシエタノールの70〜80％をアスピレ
ータ真空で取出し、残分を水500mlにとる。４
回エーテル抽出した後に、2N塩酸でPH５に調
節する。析出した沈殿物を吸引濾別し、僅かの
水冷アセトンで洗浄し、10％酢酸から再結晶す
る。更に、シリカゲルカラムに通して精製を行
なうことができる。319〜321℃で分解する（炭
化）２・４・７−トリアミノ−６−（ｐ−アセ
トキシ−フエニル）−プテリジンが得られる。
反応は、有利に、メタノール中のアルカリア
ルコラートの使用下に行なうこともできる。
２ ２・４・７−トリアミノ−６−（ｐ−２−ヒ
ドロキシエトキシフエニル）−プテリジンの製
造
金属ナトリウム460mgを撹拌下に、２−エト
キシ−エタノール150ml中に溶かす。これに順
次に撹拌しながらトリアミノ−ニトロソピリミ
ジン3.1ｇ（0.02モル）及びｐ−（２−ヒドロキ
シエトキシ）−フエニルアセトニトリル3.5ｇ
（0.02モル）を加え、撹拌しながら水浴中で60
℃に加熱する。該混合物の色は、紫色から明る
い褐色に変化する。14時間撹拌した後に、反応
は終結した。該混合物を冷却させる。未反応の
２・４・６−トリアミノ−ニトロソピリミジン
を吸引濾別し、透明な溶液を乾涸するまで濃縮
する。沈澱物を熱いアセトンにとり、石油エー
テルと混合することによつて粗生成物を沈殿さ
せる。精製は、まずブタノールから再結晶し、
次に珪酸ゲル乾燥カラム（珪酸ゲル60、
Merck社製）上で分離することによつて行な
う。２・４・７−トリアミノ−６−（ｐ−２−
ヒドロキシエトキシフエニル）−プテリジンが
黄帯褐色の結晶として得られる。
250℃で分解開始。
Rf値＝0.55で単一、珪酸ゲル薄層板上で流展剤
クロロホルム／メタノール（70：30）中。
C14H15N7O2（MG.313.3）
３ ２・４・７−トリアミノ−６−（ｐ−２・３
−ジヒドロキシ−プロポキシ−フエニル）−プ
テリジンの製造
例２の化合物と同じようにして、２・４・７
−トリアミノ−６−（ｐ−２・３−ジヒドロキ
シプロポキシ−フエニル）−プテリジンも製造
することができる。
Rf値＝0.50で単一、珪酸ゲル−薄層板上で流展
剤クロロホルム／メタノール（70：30）中。
C15H17N7O3（分子量341.3）
４ ２・４・７−トリアミノ−６−（ｐ−スクシ
ノイル−フエニル）−プテリジンの製造
乾燥アセトンにコハク酸0.63ｇ（0.0055モ
ル）、ｐ−ヒドロキシトリアムテレン1.35ｇ
（0.005モル）ならびにジシクロヘキシルカルボ
ジイミド1.12ｇ（0.05モル）を加え、14日間水
分排除下に沸騰するまで加熱する。反応を中断
し、溶剤を除去する。生じた沈殿物を数回エー
テルで洗浄する。残留する沈殿物をできるだけ
少量のDMFにとり（５〜10ml）、４倍量のアセ
トンで稀釈する。該溶液をセフアデツクス
（Sephadex）−LH20−カラム（Pharmacia社
製）上に、アセトン中に懸濁させて加える。最
終生成物は溶離する際初流出物後に現われる。
アセトン溶液を濃縮することによつて２・４・
７−トリアミノ−６−（ｐ−スクシノイル−フ
エニル）−プテリジンが得られる。
Rf値＝0.30、珪酸ゲル−薄層板上で流展剤クロ
ロホルム／メタノール（70：30）中。
５ ２・４・７−トリアミノ−６−（ｐ−アジピ
ノイル−フエニル）−プテリジンの製造
例４の化合物と同じようにして、２・４・７
−トリアミノ−６−（ｐ−アジピノイルフエニ
ル）−プテリジンも製造することができる。
Rf値＝0.31、珪酸ゲル−薄層板上で流展剤クロ
ロホルム／メタノール（70：30）中。
一般式の出発化合物の製造は、例えば次の例
によつて行なうことができる：
ｐ−（２−ヒドロキシエトキシ）−フエニルアセト
ニトリルの製造
ｐ−ヒドロキシフエニルアセトニトリル５ｇを
メチルエチルケトン250ml中に溶かす。これに、
２−ブロムエタノール７ｇ及び炭酸カリウム23ｇ
を加える。混合物を48時間還流しながら撹拌下に
加熱する。反応終結後に、炭酸カリウム及び生成
した臭化カリウムを濾別する。沈殿物をアセトン
で後洗浄し、洗浄アセトンを反応混合物と一緒に
する。
透明な溶液を10〜15mlにまで濃縮する。エーテ
ルにとり、1/100Ｎ苛性ソーダ溶液で振出する。
エーテル相を炭酸ナトリウム上で乾燥し、その後
にエーテルを留去する。ｐ−（２−ヒドロキシエ
トキシ）−フエニルアセトニトリルは黄色の油状
物として得られる。
Rf値＝0.70、珪酸ゲル−薄層板上で流展剤アセト
ン／四塩化炭素（１：１）中。
ｐ−（２・３−ジヒドロキシプロポキシ）−フエニ
ルアセトニトリルの製造
ｐ−（２−ヒドロキシエトキシ）−フエニルアセ
トニトリルと同じようにして、ｐ−（２・３−ジ
ヒドロキシプロポキシ）−フエニルアセトニトリ
ルも製造することができ、この際に苛性ソーダ溶
液での振出の代りに水での振出を行なう。生成物
は水相中に存在し、その濃縮の際に無色の結晶性
沈殿物が析出する。
Rf値＝0.60、珪酸ゲル−薄層板上で流展剤アセト
ン／四塩化炭素（１：１）中。
次の実施例は、本発明による化合物から治療剤
を調製することを説明するためのものである：
(a) 胃液抵抗性錠剤の製造
錠剤芯を製造するには、次の組成を使用する
ことができる：
２・４・７−トリアミノ−６−（ｐ−アセトキ
シフエニル）−プテリジン（作用物質） 15mg
ステアリン酸マグネシウム 10mg
タルク 12mg
エーロジル ８mg
乳糖顆粒 95mg
乳糖、微細結晶性 55mg
玉濁黍澱粉 25mg
セルロース顆粒 80mg
該成分を強力ミキサー（Lo¨dige型）中で混
合し、重量300mgの錠剤に圧縮成形する。破壊
強度6.5〜8.5（ERWEKA破壊強度試験機で測
定。水中で37℃で崩壊：2.5分）を有する錠剤
が得られる。
胃液抵抗性コーテイングをつくるには、錠剤
芯上にラツカー懸濁液を塗布する。
40℃に予備加熱した芯４Kgに、
乾燥物質30％を有するポリアクリル樹脂ラツカ
ー懸濁液 100ｇ
固形物120ｇ及び水180ｇを有する顔料懸濁液
300ｇ
を含有するラツカー懸濁液を塗布する。
ポリアクリル樹脂ラツカーは、アクリル酸エ
チルエステルとメタクリル酸（１：１）とから
の共重合体を含有する。
顔料懸濁液は次の配合物を有する：
タルク 50ｇ
二酸化チタン 63ｇ
レーキ 42ｇ
ポリエチレンワツクス 90ｇ 600゜、33％水中
乳化剤（Tween80） 30ｇ、33％水中
チロース（Tylose）C30 200ｇ、３％水中（水
溶性セルロースエーテル）
セルロース 微細結晶性 15ｇ
乳 糖 183ｇ
抑泡性エマルジヨン １ｇ
水 326ｇ
約40分のスプレー時間後に、胃液安定性＞３時
間を有する錠剤が得られる。
２・４・７−トリアミノ−６−（ｐ−アセトキ
シフエニル）プテリジンにつき記載したと同様の
方法で、一般式の他の化合物、例えば２・４・
７−トリアミノ−６−（ｐ−ヒドロキシフエニル）
−プテリジン、
２・４・７−トリアミノ−６−（ｐ−２−ヒド
ロキシエトキシフエニル）−プテリジン、
２・４・７−トリアミノ−６−（２・３−ジヒ
ドロキシ−プロポキシ−フエニル）−プテリジン、
２・４・７−トリアミノ−６−（ｐ−スクシノ
イル−フエニル）−プテリジン、
２・４・７−トリアミノ−６−（ｐ−アジピノ
イル−フエニル）−プテリジン、
も処方することができる。
腸管外投与に好適な型の医薬の製造
腸管外、殊に静脈内服用に好適な薬剤フオーム
の製造は、次のようにして行なうことができる：
２・４・７−トリアミノ−６−（ｐ−ヒドロキ
シフエニル）−プテリジン25mgに室温でジメチル
アミノエタノールの10％水溶液10mlを加える。こ
の場合、作用物質は溶解するか、ないしは溶解し
はじめる。引続き、生理的食塩水で100mlに稀釈
する。透明で帯黄色のPH10.9の溶液が得られる。
２・４・７−トリアミノ−６−（ｐ−ヒドロキ
シフエニル）プテリジンにつき記載したのと同様
の方法で、一般式の他の化合物、例えば２・
４・７−トリアミノ−６−（ｐ−アセトキシフエ
ニル）−プテリジン、
２・４・７−トリアミノ−６−（ｐ−２−ヒド
ロキシエトキシフエニル）−プテリジン、
２・４・７−トリアミノ−６−（２・３−ジヒ
ドロキシ−プロポキシ−フエニル）−プテリジン、
２・４・７−トリアミノ−６−（ｐ−スクシノ
イル−フエニル）−プテリジン、
２・４・７−トリアミノ−６−（ｐ−アジピノ
イル−フエニル）−プテリジン
も処方することができる。[Formula] also represents a group (wherein R 2 generally has the same meaning as R 1 group)] and R represents an alkali cation such as sodium or potassium (compounds of general formula A') Alternatively, it can be carried out by reacting a compound represented by the general formula A in which R represents hydrogen in the presence of an acid acceptor. The choice of methods and reaction conditions that can be used to prepare compounds of general formula B is determined in particular by the relative availability of starting materials of formula A, and, respectively, and by the probability of by-product formation (e.g. amino (by reaction of functional groups), depending on considerations regarding the ease with which separation and work-up can be carried out. For example, under the conditions of synthesis according to variant (a), the substituent R
It should be noted that is sufficiently stable. The preparation of compounds of general formula B according to process (a) can be carried out as follows: Compounds of formula are mixed with a suitable reaction medium which is inert under the reaction conditions, such as dimethyl-formamide or N.
in N-dimethyl-acetamide, in particular in the presence of alkali metal hydroxides or alkali metal amides or alkali alcoholates of lower alcohols, e.g. in alkoxyalkanols such as 2-ethoxyethanol or methanol, optionally at elevated temperature. In some cases, it is reacted with a compound of the general formula in suspension. The reaction time is generally kept as short as possible, for example when working at reflux temperatures. Post-treatment can be carried out in a conventional manner. Decomposition of the extract and/or final product can be carried out, for example, by working at the lower limits of possible reaction temperatures or by using alkali metal alcoholates with low nucleophilic properties, such as potassium tert-butoxide. It can be prevented. In this case, the preparation of compounds of general formula B by process (b) can be carried out as follows: in a suitable inert solvent, for example a nitrile such as acetonitrile, N.N-dimethylformamide, hexamethylphosphoric acid. Amides such as triamides, alcohols such as tertiary butanol, pyridine, N/N
- the general formula in a mixture or suspension of an amine such as dimethylaniline, optionally in a solvent;
Add compound A′ to room temperature and 120 °C while stirring advantageously.
or the boiling point of the solvent, optionally in a suitable solvent such as those mentioned above, optionally with an acid acceptor, such as triethylamine, N.N-dimethylaniline, N. - Added with the addition of a tertiary amine such as methylmorpholine. The reaction can be brought to completion with further stirring for a certain period of time, for example from 2 to 24 hours, after which the batch can be worked up in the customary manner. When R represents hydrogen in the compound of general formula A and when the compound Carbodiimide is used. The reaction may be carried out in a suitable absolutely anhydrous inert solvent such as acetone, pyridine, etc., especially with heating, optionally over an extended period of time, such as 14 days. The starting compounds of the general formula A', and are known or can be prepared by known methods or analogously to methods known per se. Compounds of the general formula are generally crystalline compounds with relatively high melting points (partially decomposed). The compounds can be recrystallized, for example, from aqueous solution, optionally by adding formamide, acetonitrile and optionally also by adding an acid such as formic acid, acetic acid or phosphoric acid. Compound of formula A (2,4,7-triamino-6
-(p-hydroxy-phenyl)-pteridine=
“p-hydroxy-triamterene”) and its physiologically acceptable salts, in particular sodium, potassium, lithium salts, as well as physiologically non-hazardous bases (with the same pharmacological action) and non-contraindicative amines. and guanidine, such as N-alkyl substituted ethanolamines and (basic) derivatives, and salts with propanol-2-amines and (basic) derivatives and compounds of general formula B are important pharmaceuticals. The compounds have a potassium-retaining effect and, at the same time, an excellent diuretic effect and an extrarenal, especially cardioprotective effect. p-hydroxy-triamterene is prominent. The compounds are superior to the state of the art, for example triamterene, and therefore represent a real enrichment of the technology. For a direct comparison of diuretic and potassium-retaining effects, the study by Knauf (cited above) on the epithelium of the main excretory duct of the murine submandibular lymph gland can be used. As an indicator of the cardioprotective effect, one can use, for example, the electrophysiological studies of isolated heart tissue of guinea pigs and dogs by Luderitz (supra). Furthermore, compounds of the general formula are superior to triamterene due to their better water solubility. Significantly improved water solubility is generally considered in compounds of the general formula which have groups with strong salt-forming properties (strongly basic or acidic). In this respect, mention may be made in particular of compounds of the general formula B in which an amine residue or an ammonium group is present in the β-position relative to the phenolated oxygen. Particular mention may be made of compounds of the general formula B in which q is defined such that a nitrogen atom is present in the β-position relative to the phenolated oxygen. The compounds of the general formula according to the invention with suitable therapeutic agents are therefore suitable not only for oral administration but also for parenteral administration, especially when the compounds are present in salt form. Compounds of the general formula can be dosed according to the type of indication and the individual needs of the patient. As a result of its improved diuretic effect compared to triamterene, the doses used in practice are generally lower than the doses of triamterene; therefore, the usual doses of triamterene can be considered at the upper end of the dosage range for the general formula agent. can. Pharmaceutical preparations can be prepared in a conventional manner from the new compounds and can contain the customary carriers and auxiliaries. The preparations are solid preparations suitable for oral administration, such as tablets, capsules, dragees and the like. For oral administration, pharmaceutically inert solid substances can be used as carrier materials, such as mannite, lactose, organic or inorganic calcium salts, and the like. Particularly suitable binders are polyvinylpyrrolidone, gelatin or cellulose derivatives. Other additives include tablet disintegrants such as starch or alginic acid, lubricants such as stearic acid or its salts, and inorganic flow agents such as talc or colloidal silicic acid, and taste modifiers. can be used. The active substances can be mixed with auxiliaries in the customary manner and granulated in the wet or dry state. Depending on the type of excipients used, it is also possible in some cases to obtain powders which can be made into tablets directly by simple mixing. The granules or powders can be directly packed into capsules or pressed into tablet cores in a conventional manner. For parenteral administration, therapeutic agents can similarly be prepared and administered in a conventional manner. The following examples are used to detail the preparation of compounds of general formula B, but the invention is not limited to this method. Preparation Example 1 Preparation of 2,4,7-triamino-6-(p-acetoxy-phenyl)-pteridine 410 mg of metallic sodium are dissolved in 100 ml of 2-ethoxy-ethanol under stirring. 1,100 mg of 2,4,6-triaminonitrosopyrimidine and 1,140 mg of p-acetoxybenzyl-cyanide are sequentially added to the mixture while stirring, and the mixture is heated to boiling while stirring. The color of the mixture changes from purple to brown. After boiling under reflux for 2 hours, heating is discontinued and the reaction mixture is allowed to cool. Continuing,
70-80% of the 2-ethoxyethanol is removed with an aspirator vacuum and the residue is taken up in 500 ml of water. 4
After extraction with ether, the pH was adjusted to 5 with 2N hydrochloric acid. The precipitate that has separated out is filtered off with suction, washed with a little water-cooled acetone and recrystallized from 10% acetic acid. Further, purification can be carried out by passing it through a silica gel column. 2,4,7-triamino-6-(p-acetoxy-phenyl)-pteridine is obtained which decomposes (carbonizes) at 319 DEG -321 DEG C. The reaction can also advantageously be carried out using an alkali alcoholate in methanol. 2 Preparation of 2.4.7-triamino-6-(p-2-hydroxyethoxyphenyl)-pteridine 460 mg of metallic sodium are dissolved in 150 ml of 2-ethoxy-ethanol with stirring. 3.1 g (0.02 mol) of triamino-nitrosopyrimidine and 3.5 g of p-(2-hydroxyethoxy)-phenylacetonitrile are added to this sequentially with stirring.
(0.02 mol) and 60 min in a water bath with stirring.
Heat to ℃. The color of the mixture changes from purple to light brown. After stirring for 14 hours, the reaction was complete. Allow the mixture to cool. The unreacted 2,4,6-triamino-nitrosopyrimidine is filtered off with suction and the clear solution is concentrated to dryness. The crude product is precipitated by taking up the precipitate in hot acetone and mixing with petroleum ether. For purification, first recrystallize from butanol,
Next, a silicic acid gel drying column (silicic acid gel 60,
(manufactured by Merck). 2,4,7-triamino-6-(p-2-
Hydroxyethoxyphenyl)-pteridine is obtained as yellowish-brown crystals. Decomposition starts at 250℃. Single with Rf value = 0.55, on a silicic acid gel thin plate in the flow agent chloroform/methanol (70:30). C 14 H 15 N 7 O 2 (MG.313.3) 3 2,4,7-triamino-6-(p-2,3
-dihydroxy-propoxy-phenyl)-pteridine In the same manner as for the compound of Example 2, 2,4,7
-Triamino-6-(p-2.3-dihydroxypropoxy-phenyl)-pteridine can also be produced. Single with Rf value = 0.50, on silicic acid gel-thin plate in flow agent chloroform/methanol (70:30). C 15 H 17 N 7 O 3 (molecular weight 341.3) 4 Preparation of 2,4,7-triamino-6-(p-succinoyl-phenyl)-pteridine 0.63 g (0.0055 mol) of succinic acid, p-hydroxyl in dry acetone Liam Terene 1.35g
(0.005 mol) as well as 1.12 g (0.05 mol) of dicyclohexylcarbodiimide and heated to boiling with exclusion of water for 14 days. Stop the reaction and remove the solvent. The precipitate formed is washed several times with ether. Take the remaining precipitate in as little DMF as possible (5-10 ml) and dilute with 4 volumes of acetone. The solution is applied onto a Sephadex-LH20-column (manufactured by Pharmacia), suspended in acetone. The final product appears after the initial effluent during elution.
By concentrating the acetone solution, 2.4.
7-triamino-6-(p-succinoyl-phenyl)-pteridine is obtained. Rf value = 0.30, silicic acid gel - on thin laminate in flow agent chloroform/methanol (70:30). 5 Preparation of 2,4,7-triamino-6-(p-adipinoyl-phenyl)-pteridine In the same manner as for the compound of Example 4, 2,4,7
-triamino-6-(p-adipinoylphenyl)-pteridine can also be produced. Rf value = 0.31, silicic acid gel - on thin laminate in flow agent chloroform/methanol (70:30). The starting compound of the general formula can be prepared, for example, by the following example: Preparation of p-(2-hydroxyethoxy)-phenylacetonitrile 5 g of p-hydroxyphenylacetonitrile are dissolved in 250 ml of methyl ethyl ketone. to this,
7g of 2-bromoethanol and 23g of potassium carbonate
Add. The mixture is heated under stirring at reflux for 48 hours. After the reaction is complete, potassium carbonate and the potassium bromide produced are filtered off. The precipitate is then washed with acetone and the washed acetone is combined with the reaction mixture. Concentrate the clear solution to 10-15 ml. Take up in ether and shake with 1/100N caustic soda solution.
The ether phase is dried over sodium carbonate and the ether is then distilled off. p-(2-hydroxyethoxy)-phenylacetonitrile is obtained as a yellow oil. Rf value = 0.70, silicic acid gel - on thin laminate in flow agent acetone/carbon tetrachloride (1:1). Production of p-(2,3-dihydroxypropoxy)-phenylacetonitrile p-(2,3-dihydroxypropoxy)-phenylacetonitrile is also produced in the same manner as p-(2-hydroxyethoxy)-phenylacetonitrile. In this case, shaking out with water is performed instead of shaking out with caustic soda solution. The product is present in the aqueous phase and upon its concentration a colorless crystalline precipitate separates out. Rf value = 0.60, silicic acid gel - on thin laminate in flow agent acetone/carbon tetrachloride (1:1). The following examples are intended to illustrate the preparation of therapeutic agents from the compounds according to the invention: (a) Production of gastric juice-resistant tablets To produce tablet cores, the following composition is used: Produces: 2,4,7-triamino-6-(p-acetoxyphenyl)-pteridine (active substance) 15 mg Magnesium stearate 10 mg Talc 12 mg Aerosil 8 mg Lactose granules 95 mg Lactose, microcrystalline 55 mg Millet starch 25 mg Cellulose Granules 80 mg The ingredients are mixed in a high-intensity mixer (Lo¨dige type) and compressed into tablets weighing 300 mg. Tablets are obtained with a breaking strength of 6.5-8.5 (measured with an ERWEKA breaking strength tester. Disintegration in water at 37° C.: 2.5 minutes). To create a gastric juice-resistant coating, a lacquer suspension is applied onto the tablet core. 4 kg of core preheated to 40 °C, 100 g of polyacrylic resin lacquer suspension with 30% dry matter, pigment suspension with 120 g of solid matter and 180 g of water.
A Lutker suspension containing 300 g is applied. The polyacrylic resin lacquer contains a copolymer of acrylic acid ethyl ester and methacrylic acid (1:1). The pigment suspension has the following formulation: Talc 50g Titanium dioxide 63g Lake 42g Polyethylene wax 90g 600°, 33% emulsifier in water (Tween 80) 30g Tylose C30, 3% in water (water soluble) Cellulose Microcrystalline 15 g Lactose 183 g Anti-foam emulsion 1 g Water 326 g After a spraying time of about 40 minutes, tablets with gastric juice stability >3 hours are obtained. In a similar manner as described for 2,4,7-triamino-6-(p-acetoxyphenyl)pteridine, other compounds of the general formula, such as 2,4,
7-triamino-6-(p-hydroxyphenyl)
-pteridine, 2,4,7-triamino-6-(p-2-hydroxyethoxyphenyl)-pteridine, 2,4,7-triamino-6-(2,3-dihydroxy-propoxy-phenyl)-pteridine, 2,4,7-triamino-6-(p-succinoyl-phenyl)-pteridine, 2,4,7-triamino-6-(p-adipinoyl-phenyl)-pteridine, can also be formulated. Preparation of a form of medicament suitable for parenteral administration The preparation of a drug form suitable for parenteral administration, especially intravenous administration, can be carried out as follows: 2,4,7-triamino-6-(p -Hydroxyphenyl)-pteridine (25 mg) is added with 10 ml of a 10% aqueous solution of dimethylaminoethanol at room temperature. In this case, the active substance dissolves or begins to dissolve. Subsequently, dilute to 100 ml with physiological saline. A clear, yellowish solution with a pH of 10.9 is obtained. In a similar manner as described for 2,4,7-triamino-6-(p-hydroxyphenyl)pteridine, other compounds of the general formula, such as 2,
4,7-triamino-6-(p-acetoxyphenyl)-pteridine, 2,4,7-triamino-6-(p-2-hydroxyethoxyphenyl)-pteridine, 2,4,7-triamino-6 -(2,3-dihydroxy-propoxy-phenyl)-pteridine, 2,4,7-triamino-6-(p-succinoyl-phenyl)-pteridine, 2,4,7-triamino-6-(p-adipinoyl- Phenyl)-pteridine can also be prescribed.
Claims (1)
−もしくはポリ−）ヒドロキシアルキルオキシ基
を表わすか又はカルボキシ基によつて置換された
アルカノイル基を表わす〕で示されるプテリジン
化合物。 ２ ２・４・７−トリアミノ−６−（ｐ−アセト
キシフエニル）−プテリジンである、特許請求の
範囲第１項記載の化合物。[Claims] 1 General formula B: A pteridine compound represented by the following formula: [wherein R' represents a lower alkanoyloxy group, a (mono- or poly-)hydroxyalkyloxy group, or an alkanoyl group substituted with a carboxy group]. 2. The compound according to claim 1, which is 2.4.7-triamino-6-(p-acetoxyphenyl)-pteridine.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772700073 DE2700073A1 (en) | 1977-01-03 | 1977-01-03 | PTERIDINE COMPOUNDS WITH PHARMACEUTICAL EFFECTIVENESS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5384993A JPS5384993A (en) | 1978-07-26 |
| JPS631314B2 true JPS631314B2 (en) | 1988-01-12 |
Family
ID=5998070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15864777A Granted JPS5384993A (en) | 1977-01-03 | 1977-12-28 | Novel pteridine compound and medical composition having diuretic efeect high blood pressure inhibiting effect and heart effct containing same |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5384993A (en) |
| AT (1) | AT353798B (en) |
| AU (1) | AU515140B2 (en) |
| CA (1) | CA1099714A (en) |
| CH (2) | CH633962A5 (en) |
| DD (1) | DD136837A5 (en) |
| DE (1) | DE2700073A1 (en) |
| ES (1) | ES465578A1 (en) |
| FR (2) | FR2420345B1 (en) |
| GB (2) | GB1597881A (en) |
| NL (1) | NL190573C (en) |
| SE (1) | SE436203B (en) |
| ZA (1) | ZA7812B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023052239A1 (en) | 2021-09-28 | 2023-04-06 | Ambu A/S | An endoscope |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2815442A1 (en) * | 1978-04-10 | 1979-10-18 | Roehm Pharma Gmbh | QUICKLY EFFECTIVE DIURETICS |
| DE3407695A1 (en) * | 1984-03-02 | 1985-09-12 | Röhm Pharma GmbH, 6108 Weiterstadt | PTERIDINE COMPOUNDS WITH PHARMACEUTICAL EFFECTIVENESS |
| DE3505253C2 (en) * | 1985-02-15 | 1995-04-27 | Seitz Enzinger Noll Masch | Bottle distribution station for converting a conveyed single-track bottle flow into a wide bottle flow to be removed |
| HU214331B (en) * | 1992-06-17 | 1998-03-02 | Gyógyszerkutató Intézet Kft. | Methods for producing piperazine and homopiperazine derivatives and pharmaceutical compositions containing them |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3081230A (en) | 1960-09-08 | 1963-03-12 | Smith Kline French Lab | Diuretic and antihypertensive triaminoarylpteridines |
| FR1014M (en) * | 1960-11-05 | 1961-12-26 | Smith Kline French Lab | Medicinal compositions based on 6-aryl-2,4,7-triaminopteridine. |
-
1977
- 1977-01-03 DE DE19772700073 patent/DE2700073A1/en active Granted
- 1977-10-20 AT AT748877A patent/AT353798B/en not_active IP Right Cessation
- 1977-12-28 JP JP15864777A patent/JPS5384993A/en active Granted
- 1977-12-29 ES ES465578A patent/ES465578A1/en not_active Expired
- 1977-12-29 DD DD77203010A patent/DD136837A5/en unknown
- 1977-12-30 FR FR7739798A patent/FR2420345B1/fr not_active Expired
-
1978
- 1978-01-01 CH CH1359977A patent/CH633962A5/en not_active IP Right Cessation
- 1978-01-02 SE SE7800048A patent/SE436203B/en not_active IP Right Cessation
- 1978-01-03 ZA ZA00780012A patent/ZA7812B/en unknown
- 1978-01-03 NL NL7800067A patent/NL190573C/en not_active IP Right Cessation
- 1978-01-03 GB GB67/78A patent/GB1597881A/en not_active Expired
- 1978-01-03 GB GB26630/80A patent/GB1597882A/en not_active Expired
- 1978-01-03 AU AU32140/78A patent/AU515140B2/en not_active Expired
- 1978-01-03 CA CA294,246A patent/CA1099714A/en not_active Expired
-
1980
- 1980-02-14 FR FR8003308A patent/FR2445331A1/en active Granted
-
1982
- 1982-09-06 CH CH528882A patent/CH639663A5/en not_active IP Right Cessation
Non-Patent Citations (1)
| Title |
|---|
| JOURNAL OF MEDICAL CHEMISTRY * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023052239A1 (en) | 2021-09-28 | 2023-04-06 | Ambu A/S | An endoscope |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3214078A (en) | 1979-07-12 |
| GB1597882A (en) | 1981-09-16 |
| ATA748877A (en) | 1979-05-15 |
| SE436203B (en) | 1984-11-19 |
| CA1099714A (en) | 1981-04-21 |
| FR2445331B1 (en) | 1983-01-28 |
| AT353798B (en) | 1979-12-10 |
| NL7800067A (en) | 1978-07-05 |
| NL190573C (en) | 1994-05-02 |
| DD136837A5 (en) | 1979-08-01 |
| JPS5384993A (en) | 1978-07-26 |
| GB1597881A (en) | 1981-09-16 |
| FR2420345B1 (en) | 1983-01-28 |
| FR2420345A1 (en) | 1979-10-19 |
| NL190573B (en) | 1993-12-01 |
| CH639663A5 (en) | 1983-11-30 |
| AU515140B2 (en) | 1981-03-19 |
| FR2445331A1 (en) | 1980-07-25 |
| SE7800048L (en) | 1978-07-04 |
| DE2700073C2 (en) | 1991-03-21 |
| ES465578A1 (en) | 1979-01-01 |
| CH633962A5 (en) | 1983-01-14 |
| DE2700073A1 (en) | 1978-07-13 |
| ZA7812B (en) | 1978-10-25 |
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